Anti-inflammatory agents

ABSTRACT

METHODS OF TREATING VIRIOUS CONDITIONS INVOLVING INFLAMMATION AND ITS CONCOMINANT SWELLING, TENDERNESS, DECREASED MOBILITY, PAIN, AND FEVER, EMPLOYING AN ARALKYL HYDROCARBON AS THE ACTIVE ANTI-INFLAMMATORY AGENT.

United States Patent 3,745,223 ANTI-INFLAMMATORY AGENTS Winston S.Marshall, Indianapolis, Ind., assignor to Eli Lilly and Company,Indianapolis, Ind.

No Drawing. Continuation-impart of application Ser. No. 91,559, Nov. 20,1970, which is a continuation-in-part of application Ser. No. 888,802,Dec. 29, 1969, both now abandoned. This application Mar. 29, 1971, Ser.

Int. Cl. A61k 27/00 US. Cl. 424-353 25 Claims ABSTRACT OF THE DISCLOSUREMethods of treating various conditions involving inflammation and itsconcomitant swelling, tenderness, decreased mobility, pain, and fever,employing an aralkyl hydrocarbon as the active anti-inflammatory agent.

Cross reference This application is a continuation-in-part of my pendingapplication Ser. No. 91,559, filed Nov. 20, 1970, which is acontinuation-in-part of my prior application Ser. No. 888,802, filedDec. 29, 1969, both now abandoned.

Background of the invention Mammals, both humans and animals. are knownto suffer from various conditions involving inflammation and itsconcomitant swelling, tenderness, decreased mobility, pain, and fever.While there are a number of anti-inflammatory agents which are eifectivein the symptomatic treatment of inflammatory conditions such asrheumatoid arthritis, rheumatoid spondylitis, osteoarthritis,degenerative joint diseases, and the like, such agents have been foundto have a number of undesirable side efiects, among them gastricirritation. Thus, the search for improved antiinflammatory agentscontinues.

The present invention provides a method of treating inflammation inhumans and animals by employing an appropriate aralkyl hydrocarbon asthe anti-inflammatory agent. The compounds employed in the practice ofthis invention appear to be relatively free from the serious gastricside effects produced by a number of commercially availableanti-inflammatory agents.

Summary of the invention This invention relates to a method of treatinginflammation and the resulting pain and fever in mammals, both humansand animals. More particularly, this invention provides a method oftreating inflammatory disorders which comprises administering to asubject suflering from such condition from 1 to 100 mg./kg. of bodyweight daily of an aralkyl compound represented by the formula ArRwherein:

Ar represents an aryl moiety selected from the group consisting of3-phenoxyphenyl, 4-phenoxyphenyl, 3- phenylthiophenyl, 4phenylthiophenyl, 4-cyclohexylphenyl, 4 (1 cyclohexenynphenyl, 4biphenylyl, 4 iso-butylphenyl, 4 cyclohexyl 3 chlorophenyl, 3 methyl 4phenoxyphenyl, or 3 methoxy-4- phenoxyphenyl, 4 iso-propylphenyl, 4 (1cyclooctenyl)phenyl, 4 cyclooctylphenyl, 4' fluorobir 3,745,223 PatentedJuly 10, 1973 "ice A number of the compounds represented by the aboveformula have been reported to be plasticizers (US. 2,786,040), orcooling and moderating agents for neutronic reactors (US. 2,902,425).However, their anti-inflammatory activity is wholly unexpected.

This invention also provides pharmaceutical formulations containing oneor more of the above described compounds in unit dosage form fortreating inflammatory conditions in mammals.

Detailed description of the invention According to the method of thisinvention, symptomatic relief of inflammation and the accompanyingswelling, tenderness, decreased mobility, pain and fever is providedwhen from 1 to mg./kg. of body weight daily of an aralkyl compound, asdefined herein, is administered to humans and animals suffering from aninflammatory condition by either oral or parenteral routes.

The aralkyl hydrocarbons useful in the practice of this invention arerepresented by the formula wherein:

Ar represents an aryl moiety selected from the group consisting of3-phenoxyphenyl, 4 phenoxyphenyl, 3- phenylthiophenyl, 4phenylthiophenyl, 4-cyclohexylphenyl,'4 (1 cyclohexenyl)phenyl, 4biphenylyl, 4 iso-butylphenyl, 4 cyclohexyl 3 chlorophenyl, 3 methyl 4phenoxyphenyl, or 3 methoxy 4- phenoxyphenyl, 4-iso-propylphenyl,4-(l-cyclooctenyl) phenyl, 4-cyclooctylphenyl, 4' fluorobiphenylyl, 4-tert-butylphenyl, 6 methoxy 2 naphthyl, 4 (2- norbornyl)phenyl, 5indanyl, 3 chloro 4 allyloxyphenyl, 4 n-propylphenyl, 4 n-butylphenyl,4-secbutylphenyl, 4 cyclopentylphenyl, 4 neo-pentylphenyl, 2 phenyl 5pyridyl, 4 (2 pyridyl)pheny1, 4-cyclobutylphenyl, and5-phenyl-2-thienyl; and

R represents iso-propyl, iso-propenyl, n-butyl, or iso-butyl,

with the limitations that when R is n-butyl, Ar is 4- biphenylyl, andwhen R is is0-butyl, Ar is 4-phenoxyphenyl.

Included among the compounds useful in the practice of this inventionare 3-phenoxy-a-methylstyrene 3-phenoxycumene 4-phenoxy-a-methylstyrene4-phenoxycumene 4-iso-butyldiphenyl ether 4-n-butylbiphenyl4-phenylcumene 4-iso-butyl-u-methylstyrene 4-iso-butylcumene3-pheny1thio-u-methylstyrene 4-phenylthio-a-methylstyrene 34-cyclohexyl-a-methylstyrene 4-cyclohexylcumene 3-chloro-4-cyclohexyl-a-methylstyrene 3 -methy1-4phenoxy-u-methylstyrene3 -methoxy-4-phenoxycumene 4-iso-propyl-a-methylstyrene4-iso-propylcumene 4-n-propylcumene 4n-butyl-u-methylstyrene4-sec-butyl-u-methylstyrene 1- (4-cumenyl) cyclooctene4-cyclooctylcumene 4- (4-fluorophenyl) -a-methylstyrene 4-(3-fluorophenyl )-u-methylstyrene 4- (4-fiuorophenyl) cumene 4-(3-fluorophenyl) cumene 3 -methoxy-4-phenoxy-u-methylstyrene2-iso-propenyl-G-methoxynaphthalene 4-tert-butyl-u-methylstyrene 4-(2-norborny1) cumene S-iso-propenylindane3-chloro-4-a1lyloxy-u-methylstyrene 4-cyclopentylcumene4-(1-cyclohexenyl)cumene 4-neo-pentylcumene2-phenyl-S-isopropenylpyridine Z-phenyl-S-isopropylpyridine4-cyclobutylcumene 4-phenyl-u-methylstyrene 4-cyclobutyl-a-styrene 4-2-pyridyl) cumene 2-isopropyl-5-phenylthiophene TABLE I Oral ED 5 Ar R(mg/kg.)

3-phenoxyphenyl Iso-propenyl 5 o-propyl 25 o-propenyl 15 o-propyl 6 Do-Iso-butyL- 20 4-b1phenylyL. n-Butyl. 10 o Iso-propyl. 44-1sobutylphenyl... Iso-propenyl 40 o Iso-propyl (10.. o Iso-propyl.4-(l-eyelohexenyl)phenyl .do 3methyl-4-phenoxyphenyl Iso-propenyl3-methoxy-4-phenoxyphenyl.

d-iso-propylphenyl.

Do Iso-propyl- 4-(1-eye1ooctenyl)phenyl --do.. 4-cye1ooety1phenyl -.do4'-fluorobiphenylyl Iso-propenyl o 3-methoxy-4-phenox henfi-methoxy-Z-naphthy 3-chloro-4-allyloxyphenyl- NAMOIN} bounolon wwcn4-sec-buty phenyl "do 25 4-eyclopentylphenyl. Iso-propyl.-- 504-neo-pentylphenyl do 25 4-tert-butylphenyL. Iso-propenyl 204-(2-norbornyl)phenyl Iso-propyl. 100 -indauyl Isopropenyl- 50 Generallyspeaking, the compounds employed in the p i e o his in ention a p p d yth d el 4 known in the art for the preparation of aralkyl hydrocarbons.The compounds employed herein can be prepared from an appropriatearylcarboxylic acid or acetophenone according to the following reactionschemes. Hereinbelow Ar is an aryl moiety as defined in the genericformula and R represents lower alkyl.

a Ha

Another aspect of this invention contemplates and pro vides apharmaceutical preparation in dosage unit form adapted foradministration to obtain an anti-inflammatory effect comprising perdosage unit, an anti-inflammatory effective, non-toxic amount within therange from about 50 to about 1000 milligrams of at least one compound ofthe formula as defined herein above, and a pharmaceutical diluent. Apreferred pharmaceutical formulation is one adapted for oraladministration and would include the administration of the compound insoft gelatin capsules, hard gelatin capsules, and tablet formulationsillustrated below. A preferred compound for administration in accordancewith this aspect of the invention is 4-phenylcumene, but other compoundslisted above can be substituted for part or all of the 4'phenylcumene.

The above compounds can be prepared by methods well known in the art.The following examples illustrate methods which can be employed inpreparing the compounds useful in the practice of this invention.

EXAMPLE 1 Preparation of 2-(4-biphenyly1)-2-propanol A solution of 98 g.of 4-acetylbiphenyl, dissolved in 500 ml. of ether and 500 ml. benzene,was added dropwise, with stirring, to 500 ml. of a 2.15 molar solutionof methyl magnesium chloride which had been diluted with an equal volumeof ether, at such a rate that the reaction refluxed gently. After theaddition was completed, the reaction was refluxed gently overnight.

The reaction was then allowed to cool to room temperature, and theexcess Grignard reagent was decomposed by the dropwise addition of 178ml. of a saturated ammonium chloride solution. The organic layer wasdecanted from the resulting inorganic residue and poured into ice water.The organic layer was then separated, washed with dilute SOd umbicarbonate solution and Water, and

dried over sodium sulfate. Evaporation of the solvents in vacuo left awhite solid residue which was recrystallized from hexane to yield 85 g.of 2-(4-biphenylyl)-2- propanol, M.P. 88.5-90.5 C.

Analysis.-Calcd. for C H O (percent): C, 84.87; H, 7.60. Found(percent): C, 85.01; H, 7.54. This compound can be used to prepare4-pheny1-a-methylstyrene by the method of Example 13.

EXAMPLES 2-12 The following compounds were prepared according to themethod of Example 1, from the corresponding acetophenone or substitutedbenzoate ester, using appropriate amounts of methyl magnesium halidesolution:

2-(4 phenoxyphenyl)-2-propanol, B.P. 148-152/0.2 mm.; n =1.5760, from4-phenoxyacetophenone.

Analysis.-Calcd. for C H O (percent) C, 78.92; H, 7.06. Found (percent):C, 78.91; H, 7.09.

2-(3-phenylthiophenyl) 2 propanol, B.P. l54l56/ 0.05 mm.; n =1.6132,from 3-phenylthioacetophenone.

Analysis.-Calcd. for C H 'OS (percent): C, 73.72; H, 6.60; S, 13.12.Found (percent): C, 73.46; H, 6.63; S, 13.35.

2-(4-pheny1thiophenyl)-2-pr0panol, B.P., 144-153 C./ 0.09 mm.; n=1.6154, from 4-phenylthioacetophenone.

Analysis.--Calcd. for C H OS (percent): C, 73.72; H, 6.60; S, 13.12.Found (percent): C, 73.99; H, 6.89; S, 12.91.

2-(4-iso butylpheny1)-2-propanol, B.P., 77-85/ 0.16 7

mm.; n =1.5050, from 4-iso-butylacetophenone.

Analysis.--Calcd. for C H O (percent): C, 81.20; H, 10.48. Found(percent): C, 80.97; H, 10.52.

2-(4-sec butylphenyl)-2-propanol, B.P., 73-80/0.05 mm.; n =1.5094, from4-sec-butylacetophenone.

Analysis.Ca1cd. for C H O (percent): C, 81.20; H, 10.48. Found(percent): C, 81.09; H, 10.71.

2-(4 cyclohexylphenyl)-2-propanol, M.P., 71-74" C., from4-cyclohexylacetophenone.

Analysis.-Calcd. for C H O (percent): C, 82.51; H, 10.16. Found(percent): C, 82.49; H, 10.04.

2-(3-methoxy-4-phenoxyphenyl)-2-pr0panol, B.P., 170- 177/0.07 mm.; 11=1.5762, from 3-methoxy-4-phenoxyacetophenone.

Analysis.Calcd. for C H O (percent): C, 74.39; H, 7.02. Found (percent):C, 74.58; H, 7.29.

2-(3-methyl-4-phenoxyphenyl)-2-propanol, B.P., 145- 146/0.08 mm.; n=1.5705, from 3-methyl-4-phenoxyacetophenone.

Analysis.-Calcd. for C H O (percent): C, 79.31; H, 7.49. Found(percent): C, 79.47; H, 7.63.

2-(4-tert-butylphenyl) 2 propanol, M.P., 7576.5, from ethyl4-tert-butylbenzoate.

Analysz's.Calcd. for C H O (percent): C, 81.20; H, 10.48. Found(percent): C, 80.98; H, 10.58.

2-(4' fluorobiphenylyl)-2-propanol, M.P., 110-111", from4-fluoro-4-acetylbiphenyl.

Analysis.Calcd. for C H FO (percent): C, 78.24; H, 6.57. Found(percent): C, 77.95; H, 6.79.

2 (6-methoxy-2-naphthyl)2-pr0panol, M.P., 8386, from2-acetyl-6-methoxynaphthalene.

Analysis.-Calcd. for C H O (percent): C, 77.75; H, 7.46; O, 14.79. Found(percent): C, 77.54; H, 7.22; O, 14.96. These alcohols are converted tothe u-methylstyrenes by the acid method exemplified in Example 13.

EXAMPLE 13 Preparation of 4-phenyl-a-methylstyrene A suspension of 42.4g. of 2- (4-biphenylyl)-2-propanol in 100 ml. of 4 N sulfuric acid and50 ml. of ethanol was refluxed and stirred vigorously for 1.5 hours.Then 50 ml. of ethanol was added, and the reaction was refluxed withstirring for an additional 2.5 hours. After being cooled to roomtemperature, the reaction mixture was poured into ice water andextracted with ether, benzene, and chloroform. The organic extracts werecombined, washed with sodium bicarbonate solution and water, and driedover sodium sulfate. After evaporation of the solvents in vacuo, theresidue was crystallized from hexane to yield 23.4 g. of4-phenyl-u-methylstyrene, M.P. 116-118 C.

Analysis.Calcd. for C H (percent): C, 92.74; H, 7.26. Found (percent):C, 92.45; H, 6.98.

EXAMPLES 14-2-6 The following compounds were prepared according to themethod of Example 13, using the corresponding propanol as the startingmaterial:

4-phenoxy-tat-methylstyrene, B.P., 120-126/0.08 mm.; n =1.5934, from2-(4-phenoxypheny1)-2-propan0l.

Analysis.Calcd. for C H O (percent): C, 85.68; H, 6.71. Found (percent):C, 85.44; H, 6.87.

. 3-phenylthio o: methylstyrene, B.P., 113-115 0.05 mm.; n =1.6248 whichcontained 10 percent starting carbinol as measured by NMR from2-(3-phenylthiophenyl -2-propanol.

4-phenylthio-rat-methylstyrene, B.P., 147167/0.2 mm.; n =1.6374, from2-(4-phenylthiopheny1)-2-propano1.

Analysis.-Calcd. for C H S (percent): C, 79.62; H, 6.24. Found(percent): C, 79.49; H, 6.64.

4-iso-butyl-a-methylstyrene, B.P., 75-100/0.4 mm.; n 1.5 182, from 2-(4-iso-butylphenyl) -2-propanol.

Analysis.Calcd. for C H (percent): C, 89.59; H, 10.41. Found (percent):C, 89.52; H, 10.49.

4-sec-butyl-a-methylstyrene, B.P., 52-53/0.07 mm.; 11 1.5 188, from2-(4-sec-buty1phenyl)-2-pr0pano1.

AnaZyszs.-Calcd. for C H (percent): C, 89.59; H, 10.41. Found (percent):C, 89.36; H, 10.43.

4-cyclohexyl a methylstyrene, B.P., 122-142/ 0.15 mm.; n =1.5484, from2-(4-cyclohexylphenyl)-2-propanol.

Analysis.--Calcd. for C H (percent): C, 89.94; H, 10.06. Found(percent): C, 89.70; H, 10.13.

4 (1 cycl0hexenyl)cumene, B.P., 148160/5 mm.; n 1.5452, from 1-(4-cumenyl) -1-cyclohexanol.

Analysis.Calcd. for C H (percent): C, 89.94; H, 10.06. Found (percent):C, 89.70; H, 10.13.

5 (iso-propeny1)indane, B.P., 148-151/5 mm.; n =1.5529, which waspurified by preparative vapor phase chromatography, from2-(5-indanyl)-2-propanol.

Analysis.Calcd. for C H (percent): C, 91.08; H, 8.92. Found (percent):C, 90.80; H, 8.84.

4-tert-butyl-tat-methylstyrene, B.P., 105-1 15/ 5 mm.; n =1.5 184, from2- (4-tert-butylphenyl)-2-propanol.

Analysis.-Calcd. for C H (percent): C, 89.59; H, 10.41. Found (percent):C, 89.33; H, 10.20.

3 methyl-4-phenoxy-u-methylstyrene, B.P., 125-134/ 0.08 mm.; n =1.5856,from 2 (3-methyl-4-phenoxyphenyl)-2-propanol.

Analysis.Calcd. forC H O (percent): C, 85.68; H, 7.19. Found (percent):C, 85.44; H, 7.06.

3-methoxy-4-phenoxy-tat-methylstyrene, B.P., 157160/ 0.07 mm.; n=1.5914, from 2-(3-methoxy-4-phenoxy phenyl -2-propanol.

Analysis.-Calcd. for C16H1602 (percent): C, H, 6.71. Found (percent): C,79.75; H, 6.76.

4 (4-fluorophenyl)-a-methylstyrene, M.P., 127128 from2-(4-fluorobiphenyl)-2-propanol.

zAnalysis.Calcd. for C H F (percent): C, 84.87; H, 6.17. Found(percent): C, 84.68; H, 6.45.

2 iso-propenyl-6-methoxynaphthalene, M.P. 9395 from2-(6-methoxy-2-naphthyl)-2-propano1.

Analysis.Calcd. for C H O (percent): C, 84.81; H, 7.12; 0, 8.07. Found(percent): C, 84.61; H, 7.10; 0', 8.13.

EXAMPLE 27 Preparation of 3-phenoxy-u-methylstyrene Methyl magnesiumiodide was prepared by the dropwise addition of 228 g. of methyl iodideto a stirred suspension of 36.4 g. of magnesium in 1000 ml. of ether. Asolution of 148 g. of 3-phenoxyacetophenone in 500 ml.

of ether was added dropwise, and the reaction mixture was then stirredat room temperature overnight and decomposed by the dropwise addition of265 ml. of saturated ammonium chloride solution. After water was added,the reaction mixture was extracted with ether and ethyl acetate. Thecombined organic etxracts were washed with water and dried over sodiumsulfate. Evaporation of the solvents left an oily residue which wasdistilled twice to yield 94.8 g. of 3-phenoxy-a-methylstyrene, B.P.,103- 115/0.08 mm.; 11 =1.5873.

Analysis.-Calcd. for 11 0 (percent): C, 85.68; H, 6.71. Found (percent):C, 85.69; H, 6.90.

EXAMPLES 28-29 The following compounds were prepared according to themethod of Example 27 using appropriate starting materials.

3 chloro-4-allyloxy-a-methylstyrene, B.P., 99-105/ 0.07 mm.; n =1.5623,from 3-chloro-4-allyloxyacetophenone.

Analysis.-Calcd. for C H ClO (percent): C, 69.14; H, 6.29; O, 7.68.Found (percent): C, 69.23; H, 6.20; O, 7.85.

4 n-butyl a-methylstyrene, B.P. 8488/0.05 mm.; n =1.5182, from4-n-butylacetophenone.

Analysis.-Calcd. for C H (percent): C, 89.59; H, 10.41. Found (percent):C, 89.48; H, 10.48.

EXAMPLE 30 Preparation of 1-(4-cumenyl)cyclooctene A solution of4-cumenyl magnesium bromide was prepared by the dropwise addition of asolution of 70 g. of 4-bromocumene in about 250 ml. of ether to astirred suspension of 8.75 g. of magnesium turnings in 50 ml. of etherto which a few drops of ethylene bromide had been added, at such a ratethat gentle reflux was maintained. The reaction was stirred at roomtemperature for three hours. A solution of 38 g. of cyclooctanone in 250ml. of ether was added dropwise and the reaction was refluxed overnight.After the reaction had cooled to room temperature, it was decomposed bythe cautious addition of 60 ml. of saturated ammonium chloride solution.The ether layer was separated from the thus precipitated inorganicmaterial by decantation. The inorganic residue was washed with ether andbenzene. The combined organic solutions were washed with dilutehydrochloric acid and then with 'Water and dried over sodium sulfate.After evaporation of the solvents in vacuo, the residue was distilled toyield 25.1 g. of 1-(4-cumenyl)cyclooctene, B.P., 128-140/0.l mm.; n=1.5459.

Analysis.Calcd. for C17H24 (percent): C, 89.41; H, 10.59. Found(percent): C, 89.46; H, 10.77.

EXAMPLE 31 Preparation of 2-hydroxy-2- (4-cumenyl)norbornane2-hydroxy-2-(4-cumenyl)norbornane, B.P., 137-145 0.1 mm., whichcontained a trace of 2-(4-cumenyl)-2- norbornene was prepared in amanner similar to the procedure of Example 30 using appropriate amountsof 4- bromocumene, magnesium, and norcamphor.

EXAMPLE 32 Preparation of 1-(4-cumenyl)propanol 1 (4 cumenyl)propanol,B.P., 124135/5 mm.; n =1.5789, was prepared according to the method ofExample 31 using appropriate amounts of 4-br0mocumene, propionaldehyde,and magnesium.

Analysis.-Calcd. for C H O (percent): C, 80.85; H, 10.18. Found(percent): C, 81.08; H, 9.92.

EXAMPLE 33 Preparation of 4-phenylcumene A mixture of 21.2 g. of2-(4-biphenylyl)-2-propanol, 4 5.- 9i percent Pd/C, 20 (II P 0f z e; and200 1 11.

of ethyl acetate was hydrogenated until the calculated amount ofhydrogen has been absorbed. After the catalyst was separated byfiltration, the reaction mixture was washed successively with water, 5percent NaHCO solution, and water and dried over sodium sulfate.Evaporation of the solvent in vacuo left an oily residue which wasdistilled to yield 16.3 g. of 4-phenylcumene, B.P., 112/0.09 mm.; n=1.5849.

Analysis.-Calcd. for C H (percent): C, 91.78; H, 8.22. Found (percent):C, 92.06; H, 7.97.

EXAMPLES 34-42 The following compounds were prepared according to themethod of Example 33 using the corresponding propanol benzyl alcohol, orstyrene as the starting material:

4 phenoxycumene, B.P., 104-110/0.05 mm.; n =1.5591, from2-(4-phenoxyphenyl)-2-propanol.

AnaIysis.-Calcd. for C H O (percent): C, 84.87; H, 7.60. Found(percent): C, 84.80; H, 7.38.

4-pheny1thiocumene, B.P., l35141/0.07 mm.;

from 2-(4-phenylthiophenyl)-2-propanol.

Analysis.-Calcd. for C H S (percent): C, 78.89; H, 7.06. Found(percent): C, 78.81; H, 7.16.

4-n-propylcumene, B.P., 83-89/5 mm.; n =1.4888, from 1- 4-cumenyl)l-propanol.

Analysis.-Calcd. for C, H (percent): C, 88.82; H, 11.18. Found(percent): C, 88.72; H, 10.91.

4-iso-butylcumene, B.P., 5269/0.13 mm.;

from 2-(4-iso-butylphenyl)-2-propanol.

Analysis.-Calcd. for C H (percent): C, 88.56; H,

11.44. Found (percent): C, 88.85; H, 11.34.

4-cyclopentylcumene, B.P., 130/5 mm.;

from 4- 1-cyclopentenyl) cumene.

Analysis.-Calcd. for C H (percent): C, 89.29; H, 10.71. Found (percent):C, 89.06; H, 10.79.

4-cyclohexylcumene, B.P. 105-11'0/0.l mm.;

from 2-(4-cyclohexylphenyl)-2-propanol.

Analysis.--Calcd. for C H (percent): C, 89.04; H,

10.96. Found (percent): C, 89.27; H, 10.66.

4-cyclooctylcumene, B.P., 126-134/0.1 mm.;

from 1-(4-cumenyl)cyclooctene.

AnaZysis.-Calcd. for C17H26 (percent): C, 88.62; H, 11.38. Found(percent): C, 88.38; H, 11.52.

4-(2-norbornyl)cumene, B.P., 150156/5 mm.;

from 2-hydroxy-2-(4-cumenyl)norbornane.

Analysis.-Calcd. for C H (percent): C, 89.65; H, 10.35. Found (percent):C, 89.38; H, 10.20.

4-(4-fluorophenyl)cumene, M.P., 91-94, from 2-(4'- fluorobiphenylyl)-2-propanol.

Analysis.-Calcd. for C H F (percent): C, 84.08; H, 7.06; F, 8.86. Found(percent): C, 84.02; H, 6.92; F, 8.59.

EXAMPLE 43 Preparation of 3-phenoxycumene A mixture of 21 g. of3-phenoxy-a-methylstyrene, prepared according to Example 27, 1 g. ofplatinum oxide, and 200 ml. of ethanol was hydrogenated until thecalculated amount of hydrogen had been absorbed. The catalyst wasfiltered and the filtrate was evaporated in vacuo. The residual oil wasdistilled to yield 17.1 g. of 3-phenoxycumene, B.P., -150/5 mm.; n=1.5574.

Analysis.-Calcd. for C H O (percent): C, 84.87; H, 7.60. Found(percent): C, 84.82; H, 7.51.

9 EXAMPLE 44 Preparation of 4-iso-butyldiphenyl ether A mixture of 48 g.of 4-phenoxy-iso-butyrophenone, 24 g. of 85 percent hydrazine hydrate,26.4 g. of 85 percent potassium hydroxide, and 150 ml. of diethyleneglycol was stirred and heated to 120 for one hour. The reaction mixturewas then raised to 200 for one hour, to allow volatile materials todistill out of the mixture. The reaction mixture was then allowed tocool somewhat, 20 ml. of water was added, and the reaction mixture washeated at 200 as before for an additional hour. The reaction mixture wascooled and extracted with ether. The ether extract was washed twice withwater, dried over sodium sulfate, and evaporated in vacuo. The residualoil was distilled twice to yield 29.2 g. of 4-iso-butyldiphenyl ether,B.P., 121-130/0.1 mm.; rt ==1.5461.

Analysis.Calcd. for C H O (percent): C, 84.91; H, 8.02. Found (percent):C, 84.95; H, 7.97.

EXAMPLE 45 Preparation of 4-neo-pentylcumene 4-neo-pentylcumene, B.P.,6568/0.7 mm.;

was prepared according to the method of Example 44 from4-cumenyl-tert-butyl ketone.

Analysis.Calcd. for C H (percent): C, 88.35; H, 11.65. Found (percent):C, 88.13; H, 11.42.

In the practice of this invention, one of the anti-inflammatory agentsdisclosed herein is administered to a subject suffering from aninflammatory condition in dosages of from about 1.0 to about 100 mg./kg.of body weight daily, either in single or divided doses. If divideddoses are utilized, the anti-inflammatory agent is generallyadministered every 4 to 6 hours. Since some of the antiinflamrnatoryagents used in the practice of this invention do not possess analgesicactivity, it may be preferred to administer the agent in combinationwith an analgesic agent, such as aspirin or d-propoxyphene, until suchtime as the swelling, tenderness, decreased mobility, and the like hassubsided. While oral administration is the preferred route ofadministration, the anti-inflammatory agents disclosed herein can alsobe administered parenterally or as rectal suppositories.

Since many of the compounds employed in the practice of this inventionare oils, they may first be adsorbed onto an inert carrier such as talc,silica gel, or the like before they are formulated into capsules,tablets, pills, powders, or granules. Such solid dosage forms for oraladministration can also comprise, as is normal practice, additionalsubstances other than inert diluents, e.g., lubricating agents such asmagnesium stearate. In the case of capsules, tablets, and pills, thedosage forms may also comprise buffering agents. Tablets and pills canadditionally be prepared with enteric coatings. These compounds can alsobe incorporated into soft gelatin capsules.

Liquid dosage forms for oral administration include suchpharmaceutically acceptable forms as emulsions, solutions, suspensions,syrups, and elixirs containing inert diluents commonly used in the art,such as water or a suitable oil.

In formulating the compounds of this invention in liquid dosage formsfor oral administration, it may be preferred to dilute the agent to beformulated with a suitable oil such as peanut oil, cottonseed oil,sesame oil, or corn oil or the like. Such diluted mixture comprises theinternal phase of the emulsion. Flavoring agents, sweetening agents andthe like are dissolved in water which acts as the external phase of theemulsion. Besides inert diluents, such compositions can also includeadjuvants such as wetting agents, emulsifying and suspending agents, andsweetening, flavoring, and perfuming agents.

Compositions for rectal administration or suppositories which maycontain in addition to the active substances, excipient; such as cacaobutter or a suppository wax.

The dosage of active ingredient in the compositions of this inventionmay be varied; however, it is necessary that the amount of the activeingredient shall be such that a suitable dosage form is obtained. Theselected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment.Generally, dosage levels of between 1.0 to mg./kg. of body weight dailyare administered to mammals to obtain effective relief of inflammation,pain, and with some compounds, fever. However, prescribed doses of oneor more of these compounds in a suitable formulation will probably rangefrom about 50 mg. to 1000 mg. 1 to 4 times a day depending upon thepatient body weight, the condition being treated, and other factors ofconcern to the patients physician.

EXAMPLE 46 Capsule formulation Percent 4-phenylcumene 60 Silica gel(Syloid 244 40 The 4-phenylcumene is mixed with silica gel in a suitablemixer to produce a homogeneous powder. The powder may be packed intosuitable size empty gelatin capsules for administration of the drug.Typically, a No.00 gelatin capsule has been found to hold 0.55 g.powder, equivalent to 330 mg. drug. Other ingredients may be addedaccording to the art for the purpose of improving performance ofprocessing machines, assisting in disintegration of the unit dose,improvement of compactability, etc.

Other materials, of which silica gel is only one example, may be used,either singly or in combination, to adsorb and convert the compounds ofsubject patent which are oily in nature, to a dry powder.

EXAMPLE. 47

Soft elastic capsule formulation 4-phenylcumene may be encapsulated in asoft gelatin film, either neat or mixed with a suitable liquid diluentsuch as a vegetable oil. Other ingredients may be added if required forpurposes such as improving dispersibility, promoting absorption, etc.Encapsulation may be accomplished by any suitable machine, such as theScherer rotary die machine described in Remingtons PharmaceuticalScience, 13th ed., and Well known in the art.

EXAMPLE 48 Emulsion formulation Water, q.s. 100 ml. Dose: 15 ml.,equivalent to 200 mg. drug.

Span 60 is sorbitan monostearate, Atlas Chemical Industries Inc.

Tween 60 is polyoxyalkylene derivative of sorbitan monostearate, CityChemical Corp., New York, NE.

The Span 60 and soybean oil are mixed and heated to 70 C. Tween 60 andparabens are dispersed in approximately 100 ml. water at 70 C. andsucrose is added. The oil phase is added to the aqueous phase in asuitable mixer such as a Waring Blendor and mixed to produce a milkyproduct. After cooling, the 4-pheny1cumene and peppermint oil are added,and the mixture is agitated again.

11 EXAMPLE 49 Suppository formulation Percent 4-phenylcumene 15.5 Whitewax, USP 4.0 Theobroma oil, USP 80.5

1 By weight.

White wax is dissolved in the 4-phenylcumene with the aid of gentleheat. Theobroma oil is shaved and added to the mixture slowly. After thetheobroma oil has been completely melted, with the aid of additionalheat as required, the mixture may be poured into suppository molds ofsuitable size for the desired dose; e.g., a 2.58 g. suppository of theabove mixture yields a 400 mg. dose of 4- phenylcumene.

EXAMPLE 50 Tablet formulation Percent 4-phenylcumene 15.0 Silica gel10.0 Avicel 66.0 Starch flowable 7.5 Stearic acid 1.5

Avlcel is mlcrocrystalline form of cellulose, American Viscose Corp.,Merck Index, eighth edition, page 220.

4-phenylcumene is mixed with silica gel to produce a dry powder whichmay be blended with the remaining ingredients, previously blended. Theformulation may then be compressed by a suitable tablet machine toproduce tablets of desired weight, typically 667 mg. equivalent to 100mg. 4-phenylcumene.

EXAMPLE 5 l Anti-inflammatory effect of 4-phenylcumene onultraviolet-induced erythema in guinea pigs The effects of variousformulations of 4-phenylcumene were evaluated on the development ofultraviolet-induced erythema on albino guinea pig skin. The formulationswere administered orally, rectally and subcutaneously.

Methods.--A modification of the Winder et al. (1958) method was used tomeasure the anti-inflammatory activity of this agent. Albino guinea pigsof either sex weighing 225-300 grams were shaved on the back andchemically (Nair, Lotion Hair Remover, Carter Products, New York, N.Y.)depilatated 18-20 hours before exposure to ultraviolet light. Theanimals were fasted overnight. Immediately after the guinea pigs weretreated with a test compound, a gummed notebook paper reinforcement Wasplaced on their backs and they were exposed to a high intensityultraviolet light for 7 seconds. The ultraviolet light source was aHanovia Lamp (Kromayer-Model 10) which was placed in contact with theskin of the guinea pigs back. After exposure, the reinforcements wereremoved and the back wiped clean with a water soaked gauze sponge. Theunexposed area under the reinforcement provided an area of contrast forgrading the erythema. The animals were randomized and placed in clearplastic partitioned holders 10 x 20 cm. wide and cm. high. Beginning onehour after exposure and thereafter at half-hour intervals for another 1%hours, the degree of resulting erythema was graded by an arbitraryscoring system based upon the degree of contrast and redness formed.Antiinflammatory agents delay the development of the erythema andtherefore have their greatest effect at the initial grading periods.Therefore, the scores were weighed by a factor of 4, 3, 2, and 1 at the1.0, 1.5, 2.0, and 2.5 hour scoring times respectively. The erythema wasgraded as follows:

Erythema scoring system Appearance of exposed areas Total scores fromeach treatment group of four guinea pigs were compared to the controltreatment and the percent inhibition calculated as follows:

Control-Treatment Control The formulations of Compound 65268 tested wereas follows:

X Percent inhibition Vehicle Route of administration 1 1% methylcellulose suspenslonm". Oral and subcutaneously. 2"-.- Suspension(silica gel) Oral. 3- Emulsion D0; 4 15.6% theobroma oilsuppositories--. Rectal.

Results-The oral dose of 4-phenylcumene that produces a 50% inhibitionof the erythemic response (ED in the methyl cellulose suspension wasdetermined to be 4.0 mg./kg. The response to subcutaneous administrationof this formulation was not greatly different.

The compound, when adsorbed on Silica Gel (Syloid 244) and administeredin a water suspension at a dose of 50 mg./kg. orally, produced a 92%inhibition of the erythemic response.

Emulsion: When administered orally at a dose of approximately 38rng./kg., the emulsion produced a 79% inhibition of the erythemicresponse.

The theobroma oil suppositories administered rectally at an approximatedose of 35 mg./kg. produced a 50% inhibition of the erythemic response.

Conclusions.-4-phenylcumene was found to be effective in inhibiting theerythemic response to ultraviolet-induced erythema in guinea pigs in allof the formulations tested.

References-Winder, C. V.; Wax, 1.; Burr, V.; Been, I

M.; and Posiere, C. E.: A Study of Pharmacological Influences onUltraviolet Erythema in Guinea Pigs. Arch. Int. Pharmacodyn. 116: 261,1958.

I claim:

1. The method of treating inflammatory conditions in mammals whichcomprises administering to a mammalian subject from 1 to 100 mg./kg.daily of a compound of the formula I ArR wherein Ar represents an arylmoiety selected from the group consisting of 4-cyclohexylphenyl,4-(1-cyclohexenyl) pheny l, 4-biphenylyl, 4-iso-b-utylphenyl,4-cyclohexyl- 3 chlorophenyl, 4 isopropylphenyl, 4 .(1cyclooctenyl)phenyl, 4 cyclooctylphenyl, 4' fiuorobiphenylyl,4-tert-butylphenyl, 4-(2-norbornyl)phenyl, 4-n-propylpheny'1,4-n-butylphenyl, 4-sec-butylphenyl, 4-cyclopentylphenyl,4-neo-pentylphenyl or 4-cyclobutylphenyl; and

R represents iso-propyl, iso-propenyl, iso-butyl, or n-.

butyl, with the limitations that when R is n-butyl, AI is 4-biphenylyl.2. The method of claim 1 wherein the compound is 4- phenylcumene.

3. The method of claim 1 wherein the compound is 4-iso-butyl-u-methylstyrene.

4. The method of claim 1 wherein the compound is 4- iso-butylcumene.

5. The method of claim 1 wherein the compound is 4-cyclohexyl-a-methylstyrene.

6. The method of claim 1 wherein the compound is 4- cyclohexylcumene.

7. The method of claim 1 wherein the compound is 4-cyclohexyl-3-chloro-a-methylstyrene.

8. The method of claim 1 wherein the compound is 4- iso-propylcumene.

9. The method of claim 1 wherein the compound is 4-iso-propyl-a-methylstyrene.

10. The method of claim 1 wherein the compound is 1-(4-cumeny1)cyclooctene.

11. The method of claim 1 wherein the compound is 4- cyclooctylcumene.

12. The method of claim 1 wherein the compound is 4*(4-fluorophenyl)-a-methylstyrene.

13. The method of claim 1 wherein the compound is 4-(4-fluorophenyl)cumene.

14. The method of claim 1 wherein the compound is4-tert-butyl-a-methylstyrene.

15. The method of claim 1 wherein the compound is 4-(2-norbornyl)cumene.

16. The method of claim 1 wherein the compound is 4- n-propylcumene.

17. The method of claim 1 wherein the compound is 4-n-butyl-u-methylstyrene.

18. The method of claim 1 wherein the compound is4-sec-butyl-m-methylstyrene.

19. The method of claim 1 wherein the compound is 4- cyclopentylcumene.

20. The method of claim 1 wherein the compound is 4-( l-cyclohexenyl)cumene.

21. The method of claim 1 wherein the compound is 4- neo-pentylcumene.

22. A pharmaceutical preparation in dosage unit form adapted foradministration to obtain an anti-inflammatory effect comprising perdosage unit, an anti-inflammatory efiective, nontoxic amount within therange of from about 14 to about 500 milligrams of a compound selectedfrom the group consisting of 4-phenylcumene,

4-isobutyl-a-methylstyrene,

4isobutylcumene,

4-cyclohexyl-a-methylstyrene,

4-cyclohexylcumene,

4cyclohexy1-3-chloro-a-methylstyrene,

4-isopropylcumene,

4-isopropyl-u-methylstyrene,

4-(4-cumenyl)cyclooctene,

4-cyclooctylcumene,

4- (4-fluorophenyl -a-methy1styrene,

4-tert butyl-a-methylsty-rene,

4- (2-norbornyl cumene,

4-n-propyloumene,

4-n-butyl-a-methylstyrene,

4sec-butyl-a-methylstyrene,

4-cyclopentylcumene,

4-( 1-cyclohexenyl)cumene,

4-neo-pentylcumene, and a pharmaceutical diluent.

23. A pharmaceutical preparation in accordance with claim 22 in a formadapted for oral administration.

24. A pharmaceutical preparation in accordance with claim 22 wherein thecompound is 4-phenylcumene.

25. A pharmaceutical preparation in accordance with claim 23 wherein thecompound is 4-phenylcumene.

References Cited Chem. Abst., vol. 66 (1967) 46668q.

STANLEY J. FRIEDMAN, Primary Examiner US. Cl. X.R.

@2333? UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No-5," l5 ,225 Dated July l0, 1975 I Winston S. Marshall ppears in theabove-identified patent It is certified that error a hereby corrected asshown below:

and that said Letters Patent are In Column 5, line about +7, "ED shouldbe -ED In Column' l, line dh uhjz, "H should be --H In Column 5, ine 2,"reerystal" should be --crystal--.

All in coludo6= in line 55, "89.70" should be "90.15" and "l0. 15''should be --l0.35; and in line 61, "fluorobiphenyl" should be--fl.uorobiphenylyl-.

In Column T, line 6, "etxracts" should be ---"ex tracts---.

In Column 8,. line 2, "has" should be --had-.

In Column '.lO line +9 "Science" should be ----Sciences," and in thesame column line "(5, "Blendor" should be Blender- In Column l2, line 2,"areas" should be --area--, and in the' same column, line 65,"iso-butyl" should be deleted.

All in Column 1 in line ll, the first occurrence of 1-" should be -l--;in line 21, '--ahd-- should'be added after l-(lcyclohexenyl)cumene,"3and in line 22, the comma should be a. semicolon.'

Signed and sealed this 4th day of February 1975.

(SEAL) Attest:

McCOY M.- GIBSON JR. 0. MARSHALL DANN Attesting Officer Commissioner ofPatents

